Role and targeting of PRMT5 in prostate cancer

前列腺癌是美国男性癌症死亡的第二大原因。的目的 该项目旨在开发一种新的治疗方法，通过克服 阻力雄激素受体（AR）信号传导驱动前列腺癌的发展和进展， 雄激素剥夺治疗（ADT）是局部晚期和转移性激素初治患者的标准治疗。 前列腺癌（HNPC）。不幸的是，大多数患者发生去势抵抗性前列腺癌（CRPC） 在2-3年内通过AR再激活（例如，AR过表达，AR突变，AR剪接变体），这也是 对两种下一代抗AR信号传导抑制剂（ASI）阿比特龙和 恩杂鲁胺。此外，所有这些药物均诱导AR阴性神经内分泌前列腺增生的发展。 前列腺癌（NEPC），占CRPC病例的约25%，是一种致命的晚期前列腺癌， 没有任何治疗选择的癌症。因此，迫切需要开发新的靶向方法， 前列腺癌的治疗蛋白质精氨酸甲基转移酶5（PRMT 5）是一种新出现的癌基因， 表观遗传学上抑制靶基因如肿瘤抑制因子和细胞周期抑制因子的转录， 癌细胞初步研究结果显示PRMT 5在体外和体内促进前列腺癌细胞生长 通过HNPC和CRPC细胞中AR转录的表观遗传激活。与ADT和ASI不同，PRMT 5 使用我们的体外研究，我们的新型抑制剂的抑制作用不会诱导前列腺癌细胞中NEPC的发展。 模型系统考虑到AR转录先于AR剪接以及野生型和突变体的翻译， AR蛋白，我们假设靶向PRMT 5将为AR提供一种有效和独特的治疗方法。 通过克服AR再激活机制而不诱导NEPC发展来治疗前列腺癌。到 为了验证这一假设，我们将追求以下目标。目的1将确定PRMT 5在调节AR中的作用 CRPC细胞系中的表达和细胞生长。目的2将阐明PRMT 5 调节AR转录和细胞生长以及神经内分泌分化。目标3将评估是否 PRMT 5靶向在动物模型中显示出对HNPC和CRPC的更好的治疗效果。目标4 将改善PRMT 5抑制剂的效力和药代动力学性质，同时保留其对 前列腺癌临床前研究。 影响：成功完成拟议的研究将获得关于PRMT 5 表观遗传学调节前列腺癌细胞中的AR转录，并将提供临床前证据， 靶向PRMT 5是治疗HNPC和CRPC的有效方法，而不会诱导NEPC 发展有效和特异性PRMT 5抑制剂的进一步改进和鉴定将可能导致 PRMT 5抑制剂的开发用于未来的临床试验。

Prostate cancer is the second leading cause of cancer death among American men. The objective of this project is to develop a novel therapeutic approach to treat prostate cancer by overcoming the mechanisms of resistance. Androgen receptor (AR) signaling drives prostate cancer development and progression, and androgen deprivation therapy (ADT) is the standard of care for locally advanced and metastatic hormone naïve prostate cancer (HNPC). Unfortunately, most patients develop castration resistant prostate cancer (CRPC) within 2-3 years via AR reactivation (e.g., AR overexpression, AR mutations, AR splice variants), which is also the mechanism of resistance to the two next generation anti-AR signaling inhibitors (ASI) abiraterone and enzalutamide. Further, all of these agents induce the development of AR negative neuroendocrine prostate cancer (NEPC), which constitutes approximately 25% of CRPC cases, a lethal and late stage of prostate cancer without any treatment option. Thus, there is an urgent need to develop novel targeting approaches for prostate cancer treatment. Protein arginine methyltransferase 5 (PRMT5) is an emerging oncogene that often epigenetically represses transcription of target genes such as tumor suppressors and cell cycle inhibitors in cancer cells. Preliminary findings show that PRMT5 promotes prostate cancer cell growth in vitro and in vivo via epigenetic activation of AR transcription in both HNPC and CRPC cells. Unlike ADT and ASI, PRMT5 inhibition by our novel inhibitor does not induce NEPC development in prostate cancer cells using our in vitro model system. Given that AR transcription precedes AR splicing and the translation of wild-type and mutant AR proteins, we hypothesize that targeting PRMT5 will offer an effective and unique treatment approach for prostate cancer by overcoming the mechanisms of AR reactivation without inducing NEPC development. To test this hypothesis, we will pursue the following aims. Aim 1 will determine the role of PRMT5 in regulating AR expression and cell growth in CRPC cell lines. Aim 2 will elucidate the epigenetic mechanism by which PRMT5 regulates AR transcription and cell growth as well neuroendocrine differentiation. Aim 3 will evaluate whether PRMT5 targeting demonstrates a better treatment effect for both HNPC and CRPC in animal models. Aim 4 will improve the potency and pharmacokinetic properties of PRMT5 inhibitors while preserving its specificity for prostate cancer preclinical studies. Impact: Successful completion of proposed research will gain mechanistic insight into how PRMT5 epigenetically regulates AR transcription in prostate cancer cells and will provide preclinical evidence that targeting PRMT5 is an effective approach for treatment of both HNPC and CRPC without inducing NEPC development. Further improvement and identification of potent and specific PRMT5 inhibitors will likely lead to the development of PRMT5 inhibitors for future clinical trials.